1. fMRI Studies of Motivation a. In collaboration with Dr. Falk Lohoffs Section on Clinical Genomics and Experimental Therapeutics (CGET), we analyzed Monetary Incentive Delay (MID) task data to investigate if there were any association between a number of genetic variants implicated in psychiatric disordersthe and activation in dorsal striatum during reward processing in patients with alcohol use disorder (AUD). i. Common MDD and AUD risk variant. AUD is often comorbid with other psychiatric disorders such as major depressive disorder (MDD). A locus in the TMEM161B-MEF2C region (rs10514299) has been identified as a risk variant for MDD. On the other hand, previous reports have shown the disruption of reward processing in both AD and MDD. We examined the association between rs10514299 and striatal BOLD responses during reward/loss anticipation in AUD. Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward and loss (high and low) avoidance, and a trend towards anticipation of low reward compared to healthy controls (HCs). The draft of a manuscript detailing findings of this association is prepared and being submitted for peer reviewed publication. ii. Genetic Variation in COMT Predicts Reward Processing in AUD. We have also collaborated with Dr. Lohoffs group to determine whether genetic variation in COMT in individuals with AUD and HCs is associated with differential striatal (caudate, putamen, nucleus accumbens) BOLD responses during reward processing. In this study, patients with AUD had showed significantly greater activation in regions of the ventral striatum during reward anticipation compared to controls. The AUD group also showed significantly greater activation in the caudate and nucleus accumbens during loss avoidance anticipation. Individuals with AUD who carry the minor T-allele showed significantly greater BOLD responses during reward anticipation compared to controls. This response was in opposite direction for the HCs. This finding points to the possibility using reward anticipation response as a biomarker of AUD in this variant of COMT gene. The manuscript for this study is prepared and submitted for peer reveiwe publication. iii. Effects of Dopamine Transporter (DAT) Methylation on Neural Substartes of Reward. Many studies have shown that alcohols reinforcement is mediated by dopamine signaling (modulated by DAT) in the human brain reward system. In this work with Dr. Lohoff, we investigated that methylomic variation in the DAT gene (DAT1/SLC6A3) affects DAT expression, thus contributing to differences in brainreward circuitry in individuals with alcohol dependence (ALC). The results in this study showed that decreased methylation of the promoter region of SLC6A3 predicted the activation in NAc during high loss anticipation and low loss anticipation in HC but not in individuals with ALC. This might suggest that epigenetic regulation of striatal DAT expression might be disrupted in AUD subjects (Muench et al., 2018). b. Reward Incentive Delay (RID) Task for Ghrelin Study. We analyzed the data from a study conducted by Dr. Leggios Section on Clinical Psychoneuroendocrinology and Neuropsychopharma-cology (CPN). This study used the RIDfb task, a modification of the MID task that uses food and beverage images as cues, to investigate the role of ghrelin, a neuropeptide involved in regulating hunger and reward perception, in alcohol craving and use in a population of non-treatment seeking heavy drinkers. In this task, the neural regions associated with motivation and response to reward were assessed as the participants attempted to earn points for intravenous alcohol and food rewards. Results showed that ghrelin increased the alcohol-cue signal in the amygdala and modulated the food-cue signal in the medial orbitofrontal cortex and nucleus accumbens. We also found increased resting-state connectivity between right amygdala and right mOFC prior to alcohol infusion and decrease connectivity after the alcohol infusion. The relationship between breath alcohol concentration and subjective effects of alcohol was also moderated by ghrelin. These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder (Farokhnia et al., 2017). c. Compulsivity and Reward Incentive Delay with Shock (RIDs) Task. We have conducted a novel translational study to explore the neural correlates of aversion resistant alcohol addiction using a paradigm, which adds an aversive component to the RID task. In this study, the participants (light and heavy drinkers) were able to earn points for real alcohol and food rewards at the risk of receiving a small electric shock. Compared with light drinkers, heavy drinkers attempted to earn more aversion-paired alcohol points. Fronto-striatal circuitry, including the medial prefrontal cortex, anterior insula, and striatum, was more active in this group when viewing threat-predictive alcohol cues. Heavy drinkers had increased connectivity between the anterior insula and the nucleus accumbens. Greater connectivity was associated with more attempts to earn aversion-paired alcohol points and self-reported compulsive alcohol use scores. Higher activation of fronto-striatal circuitry in heavy drinkers may be associated with compulsive alcohol seeking. This study might provide new approaches in treatment of AUD by disrupting the circuitry contributing to compulsive alcohol use (Grodin et al., 2018). 2. fMRI Studies of Decision-Making Aversive Interoceptive state and Insular Response. Craving is an interoceptive construct that underlies relapse in settings where social context is a strong modulating factor. The insula, a structure involved in higher order representation of aversive interoceptive states, has been implicated in both social stress and drug craving. Activity of the insula, as measured by fMRI, is correlated with subjective cravings and its atrophy has been shown in alcohol use disorder, but its activity within a social context is unknown. We have conducted a study utilizing a modified version of the Ultimatum Game, a paradigm where participants are given an offer which divides $20.00 between the participant and the proposer. Participants were given the option to accept or reject each offer. Here, we probed behavioral and brain responses of AUD and HC using the Ultimatum Game, which I sknown to robustly activate the insula. In agreement with an extensive literature, the presentation of perceived unfair monetary offers was associated with robust insula activations. These activations were markedly attenuated in AUD compared to HC, consistent with our findings of selective insula atrophy in alcohol addiction. Attenuated insula response in alcoholism may offer a biomarker of an impaired interoceptive. Impaired interoceptive salience attribution may contribute to the persistent pattern of harmful choices despite knowledge of adverse consequences that is characteristic of addictive disorders including alcoholism (Cortes et al., 2018). 3. Experimental fMRI Studies and Treatments BMS Trier Data Analysis. We have further analyzed the imaging data of the Trier test, a stress inducing procedure, collected during a previous study of Pexacerfont (Kwako et al. 2015). Our preliminary analyses indicate increased activation in the anterior cingulate and inferior frontal gyri in alcohol dependent patients when listening to self-referential stress scripts compared to non-self stress scripts. These differences were reduced in individuals who were treated with Pexacerfont but did not reach statistical significance. The data is still under analysis.